Department of Internal Medicine; Division of Gastroenterology, Hepatology, and Nutrition
Vanderbilt University Medical Center
Baldeep S. Pabla, MD has no real or apparant financial relationships to disclose.
Professor of Medicine
Department of Gastroenterology
Director, IBD Center
The 2019 Crohn’s & Colitis Congress revealed some interesting data regarding management approaches for IBD. In addition to discussions on proactive disease and drug monitoring, data on exciting new therapies for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC) were presented. In this commentary, we discuss data with important implications for the potential use of the IL-23 inhibitor mirikizumab and the MADCAM-1 antibody SHP647 in IBD, and updated long-term data on ustekinumab.
Mirikizumab in UC
Mirikizumab is an IL-23p19 antibody currently in phase III trials. At the Crohn’s & Colitis Congress, Sandborn and colleagues presented new data regarding health-related quality of life metrics from an earlier phase II trial that investigated mirikizumab in patients with UC.
Patients with moderate to severe UC who received mirikizumab 200-600 mg from the first dose demonstrated significantly improved scores on the inflammatory bowel disease questionnaire (IBDQ) compared with baseline and compared with the patients who received placebo. Improvement began as early as 4 weeks after beginning therapy and continued through the study’s end at Week 12. In addition, 44% to 56% of patients who received mirikizumab had IBDQ total scores ≥ 170 compared with only 30% for the placebo group.
This improvement in health-related quality of life is in keeping with previously reported clinical and endoscopic improvements observed in the treatment of UC with mirikizumab.
SHP647 in UC and CD
Additional data from 2 studies examining the use of the anti–MAdCAM-1 antibody SHP647 for the treatment of moderate to severe UC and CD were also presented.
First, Reinisch and colleagues presented data from the TURANDOT II open-label extension study of SHP647 in patients with moderate to severe UC. This study enrolled 330 patients who had completed TURANDOT I, 186 (56.4%) of whom had previously used an anti-TNF therapy. At Week 16, in the subset of patients who achieved clinical response to SHP647 in TURANDOT I (n = 154), there were high rates of clinical response (79.7% and 77.3%), clinical remission (30.4% and 40.0%) and mucosal healing (43.0% and 50.7%) in the 75-mg and 225-mg SHP647 groups, respectively. The medication was also noted to be safe with a low rate of serious infection, which was seen in 5.5% of patients. The most common serious adverse event (AE) was worsening of UC, which was seen in 10% of patients. These data are promising and suggest long-term efficacy in patients with UC who initially respond to SHP647. However, given this is only one study, these data need to be validated in other cohorts.
Second, D’Haens and colleagues presented updated data from OPERA II, a multicenter, open-label, phase II extension study examining the long-term safety and efficacy of SHP647 in patients with moderate to severe CD. As previously reported, 149 of 268 enrolled patients completed the study. A total of 53 patients (19.8%) discontinued the study drug due to AEs unrelated to the drug, with the most common AE being worsening of CD, and 15 patients (5.6%) experienced treatment-related AEs leading to drug discontinuation. In the 24-week extension, only one patient had to discontinue SHP647 due to an AE, which was deemed to be unrelated to treatment. A total of 157 patients had their dose escalated from the initial 75 mg (median time to escalation: 28 weeks), with a new steady-state level of 18,608 ng/mL observed 12 weeks after dose escalation (updated from the previously reported 16,190 ng/ mL). Decreases in high-sensitivity C-reactive protein and fecal calprotectin levels, important markers for disease monitoring, were demonstrated in both the 75-mg and 225-mg groups.
These long-term follow-up data add to previously published safety and efficacy data of SHP647 in CD and support the need for dose escalation in a significant proportion of patients.
Ustekinumab in CD
Long-term data were also presented for ustekinumab, which is currently FDA approved for the treatment of moderate to severe CD. Sandborn and colleagues presented Week 56 data from the IM-UNITI study, in which patients with clinical response following induction with IV ustekinumab in the UNITI-1 or UNITI-2 trials were randomized 1:1:1 to receive subcutaneously administered ustekinumab 90 mg every 8 weeks, ustekinumab 90 mg every 12 weeks, or placebo.
At Week 56, remission rates were 50.8% and 49.6% for patients receiving ustekinumab every 8 weeks and every 12 weeks, respectively (each P < .001 compared with placebo).
No new safety events were observed. Interestingly, the remission rate in the placebo group was markedly reduced from 35.9% at Week 44 to 27.5% at Week 56. This reduction suggests that the benefit from the single IV induction dose of ustekinumab these patients received during the UNITI-1 or UNITI-2 trials diminished rapidly during this 12-week extension period.
These findings reaffirm the efficacy and safety of ustekinumab in patients with moderate to severe CD. Further, the findings may have important implications: A single IV infusion likely has significant long-term efficacy, and in a patient receiving SC ustekinumab maintenance therapy, additional IV infusions beyond a single booster may be unlikely to benefit the patient.
In summary, these studies highlight important advances in drug development for the treatment of patients with moderate to severe UC and CD.
How will these studies and other new conference data influence your practice for patients with moderate to severe IBD? Lend your perspective in the comments section below.